Sepsis-induced lung injury is a common, highly-morbid critical illness. While advances in supportive care strategies have improved patient outcomes, mortality remains unacceptably high. As the mechanisms of sepsis-induced lung injury and subsequent repair are uncertain, few targeted pharmaceutical treatments have been developed that improve patient survival. This proposal aims to understand an endogenous lung epithelial repair response that is initiated by the processes which incite lung injury during sepsi. Our laboratory has recently discovered a novel mechanism of sepsis-induced lung injury that may initiate endogenous repair responses. Sepsis is associated with cleavage of the pulmonary endothelial glycocalyx, a heparan sulfate (HS)-rich layer of glycosaminoglycans lining the luminal endothelial surface. Degradation of the glycocalyx facilitates alveolar endothelial and epithelial injury and releases HS octasaccharides into the pulmonary vasculature. We propose that the HS octasaccharides released during septic glycocalyx degradation extravasate from the pulmonary microvasculature and access the alveolar epithelium, where they may affect alveolar epithelial growth factor signaling, specifically ERK signaling, and repair. However, whether the cleaved HS octasaccharides enhance or inhibit alveolar epithelial ERK signaling and repair is context dependent and may be dependent on both the sulfation pattern of the HS octasaccharides and the presence of competing HS on the alveolar epithelial cell surface. We will utilize state-of-the-art techniques to determine 1) if HS extravasates from the pulmonary microvasculature and accesses the alveolar epithelium during sepsis, 2) the sulfation pattern necessary for HS octasaccharides to enhance ATII cell ERK signaling and repair in vitro, and 3) if HS octasaccharides enhance ATII cell ERK signaling and lung repair during sepsis in vivo. Information gained from the proposed work will not only provide knowledge about endogenous alveolar epithelial repair mechanisms, but could also lead to the development of pharmacologic treatments to augment the pro-reparative effects of HS.